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Systematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection.

ABSTRACT: To evaluate the tolerability and liver safety profiles of the systemic antifungal agents commonly used for the treatment of invasive fungal infection, we conducted a systematic review and meta-analysis of randomized controlled trials published before 31 August 2009. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. We used the beta-binomial model to account for variation across studies and the maximum likelihood method to estimate the pooled risks. We identified 39 studies with more than 8,000 enrolled patients for planned comparisons. The incidence rates of treatment discontinuation due to adverse reactions and liver injury associated with antifungal therapy ranged widely. The pooled risks of treatment discontinuation due to adverse reactions were above 10% for amphotericin B formulations and itraconazole, whereas they were 2.5% to 3.8% for fluconazole, caspofungin, and micafungin. We found that 1.5% of the patients stopped itraconazole treatment due to hepatotoxicity. Furthermore, 19.7% of voriconazole users and 17.4% of itraconazole users had elevated serum liver enzyme levels, although they did not require treatment discontinuation, whereas 2.0% or 9.3% of fluconazole and echinocandin users had elevated serum liver enzyme levels but did not require treatment discontinuation. The results were similar when we stratified the data by empirical or definitive antifungal therapy. Possible explanations for antifungal agent-related hepatotoxicity were confounded by antifungal prescription to patients with a high risk of liver injury, the increased chance of detection of hepatotoxicity due to prolonged treatment, or the pharmacological entity.

SUBMITTER: Wang JL

PROVIDER: S-EPMC2876415 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Systematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection.

Wang Jiun-Ling JL Chang Chia-Hsuin CH Young-Xu Yinong Y Chan K Arnold KA

Antimicrobial agents and chemotherapy 20100322 6

To evaluate the tolerability and liver safety profiles of the systemic antifungal agents commonly used for the treatment of invasive fungal infection, we conducted a systematic review and meta-analysis of randomized controlled trials published before 31 August 2009. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. We used the beta-binomial model to account for variation across studies and the maximum likelihood method to estimate the poole ...[more]

PMID: 20308378

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Project description:Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting.

Project description:IntroductionInvasive fungal infections (IFIs) are a significant health problem in immunocompromised patients, resulting in substantial morbidity, mortality, and healthcare costs. Micafungin is a broad-spectrum echinocandin with activity against Candida and Aspergillus spp. This was a multicenter, non-comparative, retrospective observational study that evaluated the effectiveness and tolerability of intravenously administered micafungin for treating IFIs caused by Candida and Aspergillus spp.MethodsAdult patients in China who had received at least one dose of intravenously administered micafungin were eligible. Retrospective data (May 2008-April 2015) were extracted from patients' medical files and recorded using electronic data capture. The primary endpoint was overall success rate (patients with complete or partial response). Subgroup analyses determined effectiveness according to diagnostic certainty, fungal species, type of IFI, duration of micafungin treatment, and daily dose of micafungin. Tolerability, including the incidence of adverse events (AEs), was also assessed.ResultsOverall, 2555 patients who received at least one dose of micafungin were identified. The mean duration of treatment and mean daily dose were 10.2 days and 133.0 mg, respectively. The overall success rate was 60.8%; this was significantly higher in patients who received treatment for at least 1 week (range 67.9-71.6% [mean 69.2%]) compared with less than 1 week (47.8%; P < 0.0001), and those who received 50-100 mg (65.7%) compared with other daily doses (range 42.9-60.1% [mean 59.0%]; P = 0.0011). Success rates in Candida- and Aspergillus-infected patients were similar (61.9% and 56.8%, respectively). AEs and adverse drug reactions were observed in 36.2% and 4.5% of patients, respectively. The majority of AEs were mild, while discontinuation due to AEs was low (2.3%).ConclusionMicafungin is effective and well tolerated for the treatment of patients with IFIs in China, as demonstrated in Candida- and Aspergillus-infected adults. Subgroup analyses highlighted the potential benefits of treating IFIs with micafungin for a minimum of 1 week.Trial registrationClinicalTrials.gov identifier NCT02678598.FundingAstellas Pharma Inc.

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Systematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection.

Publications

Systematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection.

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